Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice

Abstract

Background: Tuberous sclerosis complex 1 (Tsc1) is known to regulate the development and function of various cell types, and RORγt is a critical transcription factor in the immune system. However, whether Tsc1 participates in regulating RORγt-expressing cells remains unknown.

Methods: We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1^RORγt) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis.

Results: Type 3 innate lymphoid cells (ILC3s) in Tsc1^RORγt mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1^RORγt mice exhibited spontaneous tonic-clonic seizures and died between 4 and 6 weeks after birth. At the age of 4 weeks, mice in which Tsc1 was specifically knocked out in RORγt-expressing cells had cortical neuron defects and hippocampal structural abnormalities. Notably, over-activation of neurons and astrogliosis were observed in the cortex and hippocampus of Tsc1^RORγt mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1^RORγt mice was decreased, and GABA supplementation prolonged the lifespan of the mice to some extent. Further experiments revealed the presence of a group of rare RORγt-expressing cells with high metabolic activity in the mouse brain.

Conclusions: Our study verifies the critical role of previously unnoticed RORγt-expressing cells in the brain and demonstrates that the Tsc1 signaling pathway in RORγt-expressing cells is important for maintaining brain homeostasis.

Keywords: GABA; RORγt-expressing cells; Seizure; Tsc1.